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Sildenafil reduces L-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in the rat.
Br J Pharmacol. 2007 Mar; 150(5):567-76.BJ

Abstract

BACKGROUND AND PURPOSE

Phosphodiesterase-5 inhibitors are beneficial in pulmonary hypertension and congestive heart failure, the two conditions associated with coronary heart disease and ischaemia. We investigated whether sildenafil counteracts the cardiovascular alterations induced by N -nitro-L-arginine methyl ester (L-NAME) in the rat.

EXPERIMENTAL APPROACH

Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5 mg kg-1day-1 for four weeks, either alone or with L-NAME (35-40 mg kg-1 day-1 in the drinking water). Systolic blood pressure and urinary parameters (6-keto-prostaglandin F1alpha, thromboxane B2, 8-isoprostane-prostaglandin F2 and nitrite/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia-reperfusion, and myocardial levels of guanosine 3', 5'cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings.

KEY RESULTS

Sildenafil dose-dependently prevented the rise in systolic blood pressure in L-NAME-treated rats. This activity was associated with a normalization of urinary 8-isoprostane-prostaglandin F2alpha and other biochemical parameters. In perfused hearts, the post-ischaemic ventricular dysfunction was worse in preparations from L-NAME-treated rats than in controls. Sildenafil dose-dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from L-NAME-treated rats, were restored by sildenafil. In noradrenaline-precontracted aortic rings from L-NAME-treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it.

CONCLUSION AND IMPLICATIONS

In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post-ischaemic ventricular dysfunction are associated with loss of vascular endothelium-relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels.

Authors+Show Affiliations

Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy. giuseppe.rossoni@unimi.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17245365

Citation

Rossoni, G, et al. "Sildenafil Reduces L-NAME-induced Severe Hypertension and Worsening of Myocardial Ischaemia-reperfusion Damage in the Rat." British Journal of Pharmacology, vol. 150, no. 5, 2007, pp. 567-76.
Rossoni G, Manfredi B, De Gennaro Colonna V, et al. Sildenafil reduces L-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in the rat. Br J Pharmacol. 2007;150(5):567-76.
Rossoni, G., Manfredi, B., De Gennaro Colonna, V., Berti, M., Guazzi, M., & Berti, F. (2007). Sildenafil reduces L-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in the rat. British Journal of Pharmacology, 150(5), 567-76.
Rossoni G, et al. Sildenafil Reduces L-NAME-induced Severe Hypertension and Worsening of Myocardial Ischaemia-reperfusion Damage in the Rat. Br J Pharmacol. 2007;150(5):567-76. PubMed PMID: 17245365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sildenafil reduces L-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in the rat. AU - Rossoni,G, AU - Manfredi,B, AU - De Gennaro Colonna,V, AU - Berti,M, AU - Guazzi,M, AU - Berti,F, Y1 - 2007/01/22/ PY - 2007/1/25/pubmed PY - 2007/5/11/medline PY - 2007/1/25/entrez SP - 567 EP - 76 JF - British journal of pharmacology JO - Br J Pharmacol VL - 150 IS - 5 N2 - BACKGROUND AND PURPOSE: Phosphodiesterase-5 inhibitors are beneficial in pulmonary hypertension and congestive heart failure, the two conditions associated with coronary heart disease and ischaemia. We investigated whether sildenafil counteracts the cardiovascular alterations induced by N -nitro-L-arginine methyl ester (L-NAME) in the rat. EXPERIMENTAL APPROACH: Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5 mg kg-1day-1 for four weeks, either alone or with L-NAME (35-40 mg kg-1 day-1 in the drinking water). Systolic blood pressure and urinary parameters (6-keto-prostaglandin F1alpha, thromboxane B2, 8-isoprostane-prostaglandin F2 and nitrite/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia-reperfusion, and myocardial levels of guanosine 3', 5'cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings. KEY RESULTS: Sildenafil dose-dependently prevented the rise in systolic blood pressure in L-NAME-treated rats. This activity was associated with a normalization of urinary 8-isoprostane-prostaglandin F2alpha and other biochemical parameters. In perfused hearts, the post-ischaemic ventricular dysfunction was worse in preparations from L-NAME-treated rats than in controls. Sildenafil dose-dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from L-NAME-treated rats, were restored by sildenafil. In noradrenaline-precontracted aortic rings from L-NAME-treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it. CONCLUSION AND IMPLICATIONS: In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post-ischaemic ventricular dysfunction are associated with loss of vascular endothelium-relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/17245365/Sildenafil_reduces_L_NAME_induced_severe_hypertension_and_worsening_of_myocardial_ischaemia_reperfusion_damage_in_the_rat_ L2 - https://doi.org/10.1038/sj.bjp.0707131 DB - PRIME DP - Unbound Medicine ER -